CN113943227B - Compound, pharmaceutical composition containing compound and application of compound - Google Patents

Compound, pharmaceutical composition containing compound and application of compound Download PDF

Info

Publication number
CN113943227B
CN113943227B CN202111427418.7A CN202111427418A CN113943227B CN 113943227 B CN113943227 B CN 113943227B CN 202111427418 A CN202111427418 A CN 202111427418A CN 113943227 B CN113943227 B CN 113943227B
Authority
CN
China
Prior art keywords
isopropylamino
propanol
naphthoxy
compound
application
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Active
Application number
CN202111427418.7A
Other languages
Chinese (zh)
Other versions
CN113943227A (en
Inventor
贺毅憬
王诗语
旷桂超
张雨
廖潇啸
龙菁
陈翔
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Xiangya Hospital of Central South University
Original Assignee
Xiangya Hospital of Central South University
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Xiangya Hospital of Central South University filed Critical Xiangya Hospital of Central South University
Priority to CN202111427418.7A priority Critical patent/CN113943227B/en
Publication of CN113943227A publication Critical patent/CN113943227A/en
Application granted granted Critical
Publication of CN113943227B publication Critical patent/CN113943227B/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
    • C07C217/02—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C217/04—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C217/28—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having one amino group and at least two singly-bound oxygen atoms, with at least one being part of an etherified hydroxy group, bound to the carbon skeleton, e.g. ethers of polyhydroxy amines
    • C07C217/30—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having one amino group and at least two singly-bound oxygen atoms, with at least one being part of an etherified hydroxy group, bound to the carbon skeleton, e.g. ethers of polyhydroxy amines having the oxygen atom of at least one of the etherified hydroxy groups further bound to a carbon atom of a six-membered aromatic ring
    • C07C217/32—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having one amino group and at least two singly-bound oxygen atoms, with at least one being part of an etherified hydroxy group, bound to the carbon skeleton, e.g. ethers of polyhydroxy amines having the oxygen atom of at least one of the etherified hydroxy groups further bound to a carbon atom of a six-membered aromatic ring the six-membered aromatic ring or condensed ring system containing that ring being further substituted
    • C07C217/34—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having one amino group and at least two singly-bound oxygen atoms, with at least one being part of an etherified hydroxy group, bound to the carbon skeleton, e.g. ethers of polyhydroxy amines having the oxygen atom of at least one of the etherified hydroxy groups further bound to a carbon atom of a six-membered aromatic ring the six-membered aromatic ring or condensed ring system containing that ring being further substituted by halogen atoms, by trihalomethyl, nitro or nitroso groups, or by singly-bound oxygen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
    • C07C213/08—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions not involving the formation of amino groups, hydroxy groups or etherified or esterified hydroxy groups

Abstract

The application also provides a compound, a pharmaceutical composition containing the compound and application thereof, wherein the compound comprises a compound shown in a structural formula (I), or a racemate thereof, or an enantiomer thereof, or a diastereoisomer, a solvate, a hydrate or a pharmaceutically acceptable salt thereof, R 1 Is selected from hydrogen atoms or C1-C4 alkyl; r is R 2 Selected from hydroxy, acetoxy or tosyl; r is R 3 Selected from hydrogen atoms or halogen; r is R 4 Selected from a hydrogen atom, halogen, hydroxyl, C1-C4 alkyl, amino, C1-C4 alkoxy, boric acid group, nitro, oligoethylene glycol group, glycosyl, diethylamino, sulfonamide group or carboxyl group; r is R 5 Is selected from hydrogen atom or C1-C4 alkyl. In the technical scheme of the application, compared with propranolol, the compound provided by the application has better treatment effect on tumors and lower IC50.(Ⅰ)。

Description

Compound, pharmaceutical composition containing compound and application of compound
Technical Field
The application relates to the technical field of medicines, in particular to a compound, a pharmaceutical composition containing the compound and application thereof.
Background
Cancer, also known as malignancy, is a disease caused by an imbalance in the mechanisms of cell growth and proliferation, which has become an important killer for human health.
Currently, the therapeutic dosage required for the drugs for treating cancer is large, and the drug is accompanied by large toxic and side effects, so that development of a drug with a small therapeutic dosage for cancer is highly demanded.
Disclosure of Invention
The application provides a compound, a pharmaceutical composition containing the compound and application thereof, and the compound can have better inhibition effect on tumor cells by using smaller dosage.
In a first aspect, the application also provides a compound comprising a compound of formula (I), or a racemate or enantiomer thereof, or diastereomer, solvate, hydrate or pharmaceutically acceptable salt thereof,
(Ⅰ)
R 1 is selected from hydrogen atoms or C1-C4 alkyl;
R 2 selected from hydroxy, acetoxy or tosyl;
R 3 selected from hydrogen atoms or halogen;
R 4 selected from hydrogen atomsHalogen, hydroxy, C1-C4 alkyl, amino, C1-C4 alkoxy, boric acid group, nitro, oligoethylene glycol group, glycosyl, diethylamino, sulfonamide group or carboxyl group;
R 5 is selected from hydrogen atom or C1-C4 alkyl.
In the technical scheme of the application, compared with propranolol, the compound provided by the application has better treatment effect on tumors and lower IC50.
In some embodiments of the application, the R 1 Selected from isopropyl groups.
In some embodiments of the application, the R 1 Selected from hydrogen atoms.
In some embodiments of the application, the R 2 Selected from hydroxyl groups.
In some embodiments of the application, the R 3 Selected from bromine or chlorine.
In some embodiments of the application, the R 4 Selected from bromine or chlorine.
In a second aspect, the present application also provides a pharmaceutical composition comprising:
i) A compound as described in any one of the above examples;
ii) a pharmaceutically acceptable excipient or carrier.
In some embodiments of the application, the pharmaceutical composition is formulated for intravenous, oral, subcutaneous, or intramuscular administration.
In some embodiments of the application, the formulation of the pharmaceutical composition is a solid formulation, a semi-solid formulation, or a liquid formulation.
In some embodiments of the application, the concentration of the compound in the pharmaceutical composition is 20 μm to 50 μm.
In a third aspect, the present application also provides a compound as described in any one of the above embodiments or a pharmaceutical composition as described in any one of the above embodiments for use in the manufacture of a medicament for inhibiting tumor cells.
In some embodiments of the application, the tumor cell is selected from the group consisting of a lung cancer cell, a stomach cancer cell, a colon cancer cell, a osteosarcoma cell, and a melanoma cell.
Drawings
The accompanying drawings, which are incorporated in and constitute a part of this specification, illustrate embodiments consistent with the application and together with the description, serve to explain the principles of the application.
FIG. 1 is a schematic illustration of the preparation route of 1-isopropylamino-3- (4-chloro-1-naphthoxy) -2-propanol according to some embodiments of the present application;
FIG. 2 is a hydrogen spectrum of 1-isopropylamino-3- (4-chloro-1-naphthoxy) -2-propanol according to some embodiments of the application;
FIG. 3 is a schematic illustration of the preparation route of S-1-isopropylamino-3- (4-chloro-1-naphthoxy) -2-propanol according to some embodiments of the present application;
FIG. 4 is a hydrogen spectrum of S-1-isopropylamino-3- (4-chloro-1-naphthoxy) -2-propanol according to some embodiments of the application;
FIG. 5 is a schematic illustration of the preparation route of R-1-isopropylamino-3- (4-chloro-1-naphthoxy) -2-propanol according to some embodiments of the application;
FIG. 6 is a hydrogen spectrum of R-1-isopropylamino-3- (4-chloro-1-naphthoxy) -2-propanol according to some embodiments of the application;
FIG. 7 is a graph of concentration of 1-isopropylamino-3- (4-chloro-1-naphthoxy) -2-propanol versus tumor cell viability for some embodiments of the application;
FIG. 8 is a graph of concentration of 1-isopropylamino-3- (4-chloro-1-naphthoxy) -2-propanol versus tumor cell viability for some embodiments of the application;
FIG. 9 is a graph of concentration of 1-isopropylamino-3- (4-chloro-1-naphthoxy) -2-propanol versus tumor cell viability for some embodiments of the application;
FIG. 10 is a graph of concentration of 1-isopropylamino-3- (4-chloro-1-naphthoxy) -2-propanol versus tumor cell viability for some embodiments of the application;
FIG. 11 is a graph of concentration of 1-isopropylamino-3- (4-bromo-1-naphthoxy) -2-propanol versus tumor cell viability for some embodiments of the application;
FIG. 12 is a graph of concentration of 1-isopropylamino-3- (4-bromo-1-naphthoxy) -2-propanol versus tumor cell viability for some embodiments of the application;
FIG. 13 is a graph of concentration of 1-isopropylamino-3- (4-bromo-1-naphthoxy) -2-propanol versus tumor cell viability for some embodiments of the application;
FIG. 14 is a graph of concentration of 1-isopropylamino-3- (4-bromo-1-naphthoxy) -2-propanol versus tumor cell viability for some embodiments of the application;
FIG. 15 is a schematic illustration of the preparation route of 1-isopropylamino-3- (4-bromo-1-naphthoxy) -2-propanol according to some embodiments of the application;
FIG. 16 is a hydrogen spectrum of 1-isopropylamino-3- (4-bromo-1-naphthoxy) -2-propanol according to some embodiments of the application;
FIG. 17 is a carbon spectrum of 1-isopropylamino-3- (4-bromo-1-naphthoxy) -2-propanol according to some embodiments of the application;
FIG. 18 is a mass spectrum of 1-isopropylamino-3- (4-bromo-1-naphthoxy) -2-propanol according to some embodiments of the application;
FIG. 19 is a schematic representation of the preparation route of R-1-isopropylamino-3- (4-bromo-1-naphthoxy) -2-propanol according to some embodiments of the application;
FIG. 20 is a hydrogen spectrum of R-1-isopropylamino-3- (4-bromo-1-naphthoxy) -2-propanol according to some embodiments of the application;
FIG. 21 is a carbon spectrum of R-1-isopropylamino-3- (4-bromo-1-naphthoxy) -2-propanol according to some embodiments of the application;
FIG. 22 is a mass spectrum of R-1-isopropylamino-3- (4-bromo-1-naphthoxy) -2-propanol according to some embodiments of the application;
FIG. 23 is a schematic illustration of the preparation route of S-1-isopropylamino-3- (4-bromo-1-naphthoxy) -2-propanol according to some embodiments of the present application;
FIG. 24 is a hydrogen spectrum of S-1-isopropylamino-3- (4-bromo-1-naphthoxy) -2-propanol according to some embodiments of the application;
FIG. 25 is a carbon spectrum of S-1-isopropylamino-3- (4-bromo-1-naphthoxy) -2-propanol according to some embodiments of the application;
FIG. 26 is a mass spectrum of S-1-isopropylamino-3- (4-bromo-1-naphthoxy) -2-propanol according to some embodiments of the application;
FIG. 27 is a bar graph of half inhibition concentration of 1-isopropylamino-3- (4-bromo-1-naphthoxy) -2-propanol and propranolol on different tumor cells according to some embodiments of the application.
Specific embodiments of the present application have been shown by way of the above drawings and will be described in more detail below. The drawings and the written description are not intended to limit the scope of the inventive concepts in any way, but rather to illustrate the inventive concepts to those skilled in the art by reference to the specific embodiments.
Detailed Description
For the purpose of making the objects, technical solutions and advantages of the present application more apparent, the technical solutions in the embodiments of the present application will be clearly and completely described in the following in conjunction with the embodiments of the present application, and it is apparent that the described embodiments are some embodiments of the present application, but not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the application without making any inventive effort, are intended to be within the scope of the application.
It should also be noted that the term "C1-C4 alkyl" as used herein refers to saturated aliphatic hydrocarbon groups, including straight and branched chain groups of 1 to 4 carbon atoms, and also straight and branched chain groups of 1 to 4 carbon atoms, such as methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl, tert-butyl.
The term "C1-C4 alkoxy" as used herein refers to an alkyl group bonded to the remainder of the molecule through an ether oxygen atom, i.e., an alkoxy group is an alkoxy group having 1 to 4 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy and sec-butoxy. As used herein, "C1-C4 alkoxy" also includes unsubstituted and substituted alkoxy groups, especially alkoxy groups substituted with one or more halogens.
The term "halogen" as used herein refers to fluorine, chlorine, bromine or iodine.
The term "pharmaceutically acceptable salt" as used herein means a salt which is not particularly limited as long as it is pharmaceutically acceptable, and includes inorganic salts and organic salts. Specifically, salts of the compounds of the present application with acids may be mentioned, and suitable salts-forming acids include, but are not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, phosphoric acid, nitric acid, phosphoric acid, and the like, organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, trifluoroacetic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, ethanesulfonic acid, and the like, and acidic amino acids such as aspartic acid, glutamic acid, and the like.
The compounds of the application contain at least two asymmetric carbon atoms (optical centers) and thus racemates, diastereomers and individual isomers are included within the scope of the present application. According to the R, S system naming convention (the kann-english-prasugrel convention), the configuration of an asymmetric carbon atom is related to the size of the substituent to which it is attached, and the difference in the size of the substituent may result in the same asymmetric carbon atom in the same series of compounds having a different R or S, but the spatial orientation of the asymmetric carbon atom substituent is unchanged.
Representative compound names in the compound shown in the structural formula (I) provided by the application are as follows:
(Ⅰ)
1-isopropylamino-3- (4-chloro-1-naphthoxy) -2-propanol.
S-1-isopropylamino-3- (4-chloro-1-naphthoxy) -2-propanol.
R-1-isopropylamino-3- (4-chloro-1-naphthoxy) -2-propanol.
1-isopropylamino-3- (4-bromo-1-naphthoxy) -2-propanol.
S-1-isopropylamino-3- (4-bromo-1-naphthoxy) -2-propanol.
R-1-isopropylamino-3- (4-bromo-1-naphthoxy) -2-propanol.
1-isopropylamino-3- (2, 4-dibromo-1-naphthoxy) -2-propanol.
S-1-isopropylamino-3- (2, 4-dibromo-1-naphthoxy) -2-propanol.
R-1-isopropylamino-3- (2, 4-dibromo-1-naphthoxy) -2-propanol.
1-isopropylamino-3- (4-fluoro-1-naphthoxy) -2-propanol.
S-1-isopropylamino-3- (4-fluoro-1-naphthoxy) -2-propanol.
R-1-isopropylamino-3- (4-fluoro-1-naphthoxy) -2-propanol.
1-isopropylamino-3- (6-hydroxy-1-naphthoxy) -2-propanol.
S-1-isopropylamino-3- (6-hydroxy-1-naphthoxy) -2-propanol.
R-1-isopropylamino-3- (6-hydroxy-1-naphthoxy) -2-propanol.
1-isopropylamino-3- (6-methoxy-1-naphthoxy) -2-propanol.
S-1-isopropylamino-3- (6-methoxy-1-naphthoxy) -2-propanol.
R-1-isopropylamino-3- (6-methoxy-1-naphthoxy) -2-propanol.
1-isopropylamino-3- (4-methoxy-1-naphthoxy) -2-propanol.
S-1-isopropylamino-3- (4-methoxy-1-naphthoxy) -2-propanol.
R-1-isopropylamino-3- (4-methoxy-1-naphthoxy) -2-propanol.
1-isopropylamino-3- (4-methyl-1-naphthoxy) -2-propanol.
S-1-isopropylamino-3- (4-methyl-1-naphthoxy) -2-propanol.
R-1-isopropylamino-3- (4-methyl-1-naphthoxy) -2-propanol.
1-isopropylamino-3- (4-boronic acid-1-naphthoxy) -2-propanol.
S-1-isopropylamino-3- (4-boronic acid-1-naphthoxy) -2-propanol.
R-1-isopropylamino-3- (4-boronic acid-1-naphthoxy) -2-propanol.
1-isopropylamino-3- (4-oligoethylene glycol-1-naphthoxy) -2-propanol.
S-1-isopropylamino-3- (4-oligoethylene glycol-1-naphthoxy) -2-propanol.
R-1-isopropylamino-3- (4-oligoethylene glycol-1-naphthoxy) -2-propanol.
1-isopropylamino-3- (4-glycosyl-1-naphthoxy) -2-propanol.
S-1-isopropylamino-3- (4-glycosyl-1-naphthoxy) -2-propanol.
R-1-isopropylamino-3- (4-glycosyl-1-naphthoxy) -2-propanol.
1-isopropylamino-3- (4-amino-1-naphthoxy) -2-propanol.
S-1-isopropylamino-3- (4-amino-1-naphthoxy) -2-propanol.
R-1-isopropylamino-3- (4-amino-1-naphthoxy) -2-propanol.
1-isopropylamino-3- (4-nitro-1-naphthoxy) -2-propanol.
S-1-isopropylamino-3- (4-nitro-1-naphthoxy) -2-propanol.
R-1-isopropylamino-3- (4-nitro-1-naphthoxy) -2-propanol.
1-isopropylamino-3- (4-diethylamino-1-naphthoxy) -2-propanol.
S-1-isopropylamino-3- (4-diethylamino-1-naphthoxy) -2-propanol.
R-1-isopropylamino-3- (4-diethylamino-1-naphthoxy) -2-propanol.
1-isopropylamino-3- (4-sulfonamide-1-naphthoxy) -2-propanol.
S-1-isopropylamino-3- (4-sulfonylamino-1-naphthoxy) -2-propanol.
R-1-isopropylamino-3- (4-sulfonylamino-1-naphthoxy) -2-propanol.
1-isopropylamino-3- (4-carboxy-1-naphthoxy) -2-propanol.
S-1-isopropylamino-3- (4-carboxy-1-naphthoxy) -2-propanol.
R-1-isopropylamino-3- (4-carboxy-1-naphthoxy) -2-propanol.
Process for the preparation of the compounds of the application
The compounds of the present application and their various intermediates can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthetic methods, and equivalent alternatives well known to those skilled in the art, preferred embodiments including but not limited to the examples of the present application.
The process for preparing the compound of the general formula (I) of the present application is specifically described below, but these specific processes do not limit the present application in any way.
The compound of the general formula (I) of the present application can be produced by the following method, however, the conditions of the method, such as reactants, solvents, amounts of the compounds used, reaction temperature, time required for the reaction, etc., are not limited to the following explanation. The compounds of the present application may also optionally be conveniently prepared by combining the various synthetic methods described in this specification or known in the art, such combination being readily apparent to those skilled in the art to which the present application pertains.
Example 1
The embodiment provides a preparation method of a 1-isopropylamino-3- (4-chloro-1-naphthoxy) -2-propanol compound, wherein the synthetic route is shown in figure 1, and specifically comprises the following steps:
propranolol hydrochloride (147.9 mg,5 mmol), N-chlorosuccinimide (79.8 mg,0.6 mmol) and dimethyl sulfoxide (79.8 mg,0.6 mmol) were dissolved in CHCl at 25deg.C 3 Reaction for 12h (2 mL) afforded 110.2mg (75%) of 1-isopropylamino-3- (4-chloro-1-naphthoxy) -2-propanol (dichloromethane/methanol=5:1) as a white solid.
The nuclear magnetic resonance hydrogen spectrum data of 1-isopropylamino-3- (4-chloro-1-naphthoxy) -2-propanol are as follows, and can be seen in FIG. 2:
1H NMR(500M Hz，Chloroform-d)：δ 8.22(d，J=8.3Hz，1.2Hz，1H)，8.12(d，1H)，7.52(ddd，J=8.4Hz，6.7Hz，1.3Hz，1H)，7.45(ddd，J=8.2Hz，6.8Hz，1.3Hz，1H)，7.27(d，1H)，6.44(d，J=8.3Hz，1H)，4.74~4.64(m，1H)，4.07(dd，J=9.6Hz，4.7Hz，1H)，3.99(dd，J=9.6Hz，5.6Hz，1H)，3.43~3.34(m，1H)，3.28(dd，J=12.3Hz，2.6Hz，1H)，3.18(dd，J=12.3Hz，9.9Hz，1H)，1.39(dd，J=9.1Hz，6.5Hz，6H)。
example 2
The embodiment provides a preparation method of an S-1-isopropylamino-3- (4-chloro-1-naphthyloxy) -2-propanol compound, wherein the synthetic route is shown in figure 3, and the preparation method specifically comprises the following steps:
s-propranolol hydrochloride (147.9 mg,0.5 mmol), NCS (79.8 mg,0.6 mmol) and dimethyl sulfoxide (7. Mu.L, 0.1 mmol) in 2mL of CHCl 3 In solution, reaction was carried out at 25℃for 12h, affording 110.2mg (75%) of S-1-isopropylamino-3- (4-chloro-1-naphthoxy) -2-propanol hydrochloride (DCM/MeOH=5:1) as a white solid.
The nuclear magnetic resonance hydrogen spectrum data of the S-1-isopropylamino-3- (4-chloro-1-naphthoxy) -2-propanol compound is as follows, and can be seen in FIG. 4:
1H NMR(500MHz，Methanol-d4)：δ 6.77(d，J=8.4Hz，1H)，6.48(d，J=8.5Hz，1H)，5.92(d，J=8.2Hz，1H)，5.81(t，J=7.4Hz，1H)，5.73(t，J=7.5Hz，1H)，5.29(d，J=8.3Hz，1H)，2.71(s，1H)，2.50(s，1H)，1.78–1.74(m，533H)。
example 3
The embodiment provides a preparation method of an R-1-isopropylamino-3- (4-chloro-1-naphthyloxy) -2-propanol compound, wherein the synthetic route is shown in figure 5, and the preparation method specifically comprises the following steps:
r-propranolol hydrochloride (147.9 mg,0.5 mmol), NCS (79.8 mg,0.6 mmol) and dimethyl sulfoxide (7. Mu.L, 0.1 mmol) in 2mL of CHCl 3 In solution, reaction was carried out at 25℃for 12h, affording 110.2. 110.2mg (75%) of S-1-isopropylamino-3- (4-chloro-1-naphthoxy) -2-propanol hydrochloride (DCM/MeOH=5:1) as a white solid.
The nuclear magnetic resonance hydrogen spectrum data of the R-1-isopropylamino-3- (4-chloro-1-naphthoxy) -2-propanol compound is as follows, and can be seen in FIG. 6:
1H NMR(500MHz，Methanol-d4)：δ 6.74(d，J=8.4Hz，1H)，6.54(d，J=8.4Hz，1H)，6.02(t，J=7.6Hz，1H)，5.95(t，J=7.7Hz，1H)，5.87(d，J=8.2Hz，1H)，5.28(d，J=8.2Hz，1H)，2.77(dq，J=9.0，4.5Hz，1H)，2.58(t，J=4.6Hz，2H)，1.80–1.68(m，746H)。
example 4
The example provides a preparation method of a 1-isopropylamino-3- (4-bromo-1-naphthoxy) -2-propanol compound, and the synthetic route is shown in fig. 15, and specifically comprises the following steps:
2-Propranolol hydrochloride (147.9 mg,0.5 mmol), HBr (40%, 178.1mg,1.1 mmol) and dimethyl sulfoxide (78. Mu.L, 0.55 mmol) were reacted in 3mL of EtOAc at 60℃for 15min to give 188.4mg (90%) of 1-isopropylamino-3- (4-bromo-1-naphthoxy) -2-propanol bromate as a white solid.
The nuclear magnetic resonance hydrogen spectrum data of 1-isopropylamino-3- (4-bromo-1-naphthoxy) -2-propanol are as follows, see fig. 16:
1H NMR(400MHz，MeOD)：δ 8.38(d，1H)，8.16(d，1H)，7.72(d，J=8.2Hz，1H)，7.66(ddd，J=8.4，6.8，1.4Hz，1H)，7.59(ddd，J=8.2，6.9，1.3Hz，1H)，6.91(d，J=8.3Hz，1H)，4.45(dtd，J=10.0，5.2，3.0Hz，1H)，4.25(t，J=5.3Hz，2H)，3.59–3.48(m，1H)，3.42(dd，J=12.7，3.0Hz，1H)，3.35–3.23(m，3H)，1.42(dd，J=6.6，5.0Hz，6H)。
carbon spectrum data of 1-isopropylamino-3- (4-bromo-1-naphthoxy) -2-propanol are as follows, see fig. 17:
13C NMR(500MHz，MeOD)：δ 152.35，130.68，127.82，126.04，125.00，124.72，124.31，120.66，111.51，104.13，68.49，63.96，49.24，45.60，16.57，15.99。
mass spectrum data of 1-isopropylamino-3- (4-bromo-1-naphthoxy) -2-propanol are as follows, see fig. 18.
Example 5
The embodiment provides a preparation method of an R-1-isopropylamino-3- (4-bromo-1-naphthoxy) -2-propanol compound, wherein the synthetic route is shown in fig. 19, and the preparation method specifically comprises the following steps:
propranolol hydrochloride (147.9 mg,0.5 mmol), HBr (40%, 178.1mg,1.1 mmol) and dimethyl sulfoxide (78. Mu.L, 0.55 mmol) were reacted in 3mL of EtOAc at 60℃for 15min to give 188.4mg (90%) of R-1-isopropylamino-3- (4-bromo-1-naphthoxy) -2-propanol bromate as transparent crystals.
The nuclear magnetic resonance hydrogen spectrum data of R-1-isopropylamino-3- (4-bromo-1-naphthoxy) -2-propanol is as follows, see fig. 20:
1H NMR(500MHz，Methanol-d4)：δ 6.77(d，J=8.4Hz，1H)，6.54(d，J=8.5Hz，1H)，6.10(d，J=8.2Hz，1H)，6.04(t，J=7.4Hz，1H)，5.98(t，J=7.5Hz，1H)，5.29(d，J=8.3Hz，1H)，2.86(dd，J=9.2，4.1Hz，2H)，2.69–2.56(m，6H)，1.78–1.74(m，5917H)。
carbon spectrum data for R-1-isopropylamino-3- (4-bromo-1-naphthoxy) -2-propanol are as follows, see fig. 21:
13C NMR(500MHz，MeOD)：δ 152.40，130.76，127.82，126.05，125.05，124.78，124.31，120.59，111.57，104.13，68.49，63.98，49.22，46.95，45.58，16.51，15.92。
mass spectrum data of R-1-isopropylamino-3- (4-bromo-1-naphthoxy) -2-propanol are as follows, see fig. 22:
example 6
The embodiment provides a preparation method of an S-1-isopropylamino-3- (4-bromo-1-naphthoxy) -2-propanol compound, wherein the synthetic route is shown in fig. 23, and specifically comprises the following steps:
s-propranolol hydrochloride (147.9 mg,0.5 mmol), HBr (40%, 178.1mg,1.1 mmol) and dimethyl sulfoxide (78. Mu.L, 0.55 mmol) were reacted in 3mL of EtOAc at 60℃for 15min to give 188.4mg (90%) of S-1-isopropylamino-3- (4-bromo-1-naphthoxy) -2-propanol bromate as transparent crystals.
The nuclear magnetic resonance hydrogen spectrum data of S-1-isopropylamino-3- (4-bromo-1-naphthoxy) -2-propanol is as follows, see fig. 24:
1H NMR(500MHz，Methanol-d4)：δ 6.77(d，J=8.4Hz，1H)，6.54(d，J=8.5Hz，1H)，6.10(d，J=8.2Hz，1H)，6.04(t，J=7.4Hz，1H)，5.98(t，J=7.5Hz，1H)，5.29(d，J=8.3Hz，1H)，2.86(s，1H)，2.63(dd，J=9.2，4.1Hz，2H)，1.78–1.74(m，822H)。
carbon spectrum data for S-1-isopropylamino-3- (4-bromo-1-naphthoxy) -2-propanol are as follows, see fig. 25:
13C NMR(500MHz，MeOD)：δ 152.40，130.75，127.82，126.05，125.05，124.77，124.31，120.59，111.56，104.13，68.49，63.98，49.22，45.58，16.51，15.92。
carbon spectrum data of S-1-isopropylamino-3- (4-bromo-1-naphthoxy) -2-propanol are shown below, see fig. 26.
In a second aspect, the present application also provides a pharmaceutical composition comprising:
i) A compound of any one of the above embodiments;
ii) a pharmaceutically acceptable excipient or carrier.
In the technical scheme of the application, the compound shown in the structural formula (I) or a racemate, an enantiomer, a solvate, a hydrate or a pharmaceutically acceptable salt thereof has excellent inhibition effect on tumor cells because the compound has excellent inhibition effect on tumor cells, and the pharmaceutical composition containing the compound as a main active ingredient has excellent inhibition effect on tumor cells.
The compound of the present application has a better inhibitory effect on tumor cells than propranolol and a lower IC50 at the same administration dose. Accordingly, the pharmaceutical composition of the present application may use a pharmaceutically acceptable excipient or carrier, and the compound of the structural formula (i) of the present application, or a racemate thereof, or an enantiomer thereof, or a diastereomer, solvate, hydrate or a pharmaceutically acceptable salt thereof, as an active ingredient.
The pharmaceutical compositions of the present application comprise a safe, effective amount of a compound of the present application within a range of pharmaceutically acceptable excipients or carriers. Wherein "safe, effective amount" means: the amount of the compound is sufficient to significantly improve the condition without causing serious side effects. The safe and effective amount of the compound is determined according to the specific conditions such as age, illness and treatment course of the subject.
"pharmaceutically acceptable excipient or carrier" means: one or more compatible solid or liquid filler or gel materials which are suitable for human use and must be of sufficient purity and sufficiently low toxicity. "compatible" as used herein means that the components of the composition are capable of blending with and between the compounds of the present application without significantly reducing the efficacy of the compounds. Examples of pharmaceutically acceptable excipients or carrier moieties are cellulose and its derivatives (e.g. sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate and the like), gelatin, talc, solid lubricants (e.g. stearic acid, magnesium stearate), calcium sulphate, vegetable oils (e.g. soybean oil, sesame oil, peanut oil, olive oil and the like), polyols (e.g. propylene glycol, glycerol, mannitol, sorbitol and the like), emulsifying agents (e.g. tween), wetting agents (e.g. sodium lauryl sulphate), colouring agents, flavouring agents, stabilisers, antioxidants, preservatives, pyrogen-free water and the like.
The compounds of the present application may be administered orally, rectally, parenterally (intravenously, intramuscularly or subcutaneously), topically.
Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compound, the liquid dosage forms may contain inert diluents commonly employed in the art, such as water or other solvents, solubilizing agents and emulsifiers, for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1, 3-butylene glycol, dimethylformamide.
In addition to these inert diluents, the compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and nonaqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.
The compounds of the application may be administered alone or in combination with other pharmaceutically acceptable compounds.
When a pharmaceutical composition is used, a safe and effective amount of a compound of the present application is administered to a mammal in need of treatment, wherein the dosage is that which is pharmaceutically considered to be effective, e.g., the concentration of the compound of the present application in the pharmaceutical composition containing it may be 20 μm to 50 μm. Of course, the particular dosage should also take into account factors such as the route of administration, the health of the patient, etc., which are within the skill of the skilled practitioner.
In a third aspect, the present application also provides a compound according to any one of the above embodiments or a pharmaceutical composition according to any one of the above embodiments for use in the manufacture of a medicament for inhibiting tumor cells.
In some embodiments of the application, the tumor cell is selected from the group consisting of a lung cancer cell, a stomach cancer cell, a colon cancer cell, a osteosarcoma cell, and a melanoma cell.
The use of the compounds provided by the present application is described in detail below.
Conventional cell culture
Cell lines H1299 (human lung cancer cells), A549 (human lung cancer cells), MGC803 (human stomach cancer cells), SW480 (human colon cancer cells), HT29 (human colon cancer cells), MKN45 (human stomach cancer cells) were cultured in RPMI-1640 medium containing 1% diabody (penicillin, streptomycin) and 10% FBS (fetal bovine serum).
Cell lines MG63 (human osteosarcoma cells), 143B (human osteosarcoma cells), ACHN (human renal cell adenocarcinoma cells), a375 (human melanoma cells), SK28 (human melanoma cells) were cultured in DMEM medium containing 1% diabody (penicillin, streptomycin) and 10% fbs (fetal bovine serum).
Culturing in a sterile constant temperature cell incubator at the temperature of 37 ℃ for a period of time, observing under a microscope that the cell density reaches 80% -90%, removing culture supernatant, washing twice with sterile PBS (without calcium and magnesium), removing washing liquid, adding 1mL of 0.125% pancreatin, covering, putting into the incubator for proper time (1 min-2 min), observing under a microscope that most cells retract and some cells fall off, and adding the complete culture medium to stop digestion. The pipette gently blows the adherent cells several times to try to make the cells in a single cell state. The cell suspension was centrifuged at 800rpm for 5min and the supernatant was discarded. The new culture bottle is used for re-suspending the cells, the cells are placed in a constant temperature incubator for continuous culture, the corresponding complete culture medium is replaced for continuous culture after 24 hours after the cells are completely attached, the cell state is closely concerned, and if the cells are polluted or suspected to be polluted, the cells are treated in time so as to avoid adverse effects on subsequent experiments.
CCK8 method for detecting cell viability
Cells in logarithmic growth phase H1299, A549, MGC803, SW480, HT29, MKN45, MG63, 143B, ACHN, A375, SK28 were collected, centrifuged and resuspended in an appropriate amount of complete medium. After cell counting, diluting to a proper concentration by using a culture medium, sequentially inoculating 3000-5000 cells in each 100 mu L cell suspension into a 96-well plate by using a row gun, and setting 3 multiple wells. After the culture plates are placed in an incubator for pre-culturing for 24 hours, absorbing and discarding the culture medium, adding 1-isopropylamino-3- (4-chloro-1-naphthyloxy) -2-propanol and 1-isopropylamino-3- (4-bromo-1-naphthyloxy) -2-propanol with different concentrations, continuously culturing for 24 hours and 48 hours, discarding the culture medium, respectively adding 100 mu L of culture medium (containing 10 mu L of LCCK8 reagent and containing no serum) under the dark condition, incubating for 1-2 hours at 37 ℃ in dark condition, measuring absorbance (OD value) at 450nm by using an enzyme-labeling instrument, analyzing the relative proliferation rate of cells according to instructions, and independently repeating the experiment for 3 times, wherein the experimental result is shown in figures 3-10.
Experimental results
1) 1-isopropylamino-3- (4-chloro-1-naphthyloxy) -2-propanol for inhibiting cell viability of lung cancer, osteosarcoma, gastric cancer and colon cancer
As a result of measurement of cell viability by CCK8 assay, as shown in FIGS. 7 to 10, cell viability of the 1-isopropylamino-3- (4-chloro-1-naphthoxy) -2-propanol treated group was decreased in concentration by 0. Mu.M, 5. Mu.M, 12.5. Mu.M, 25. Mu.M, 50. Mu.M, and 100. Mu.M 1-isopropylamino-3- (4-chloro-1-naphthoxy) -2-propanol treated group after treatment with H1299, A549, MG63, 143B, MGC803, and SW480 cells for 24 hours and 48 hours, respectively.
2) 1-isopropylamino-3- (4-bromo-1-naphthoxy) -2-propanol inhibits melanoma, osteosarcoma, gastric cancer, colon cancer, and renal cancer cell viability
As a result of measurement of cell viability by CCK8 experiments, as shown in FIGS. 11 to 15, cell viability was decreased in the 1-isopropylamino-3- (4-bromo-1-naphthoxy) -2-propanol treated groups after 0. Mu.M, 5. Mu.M, 12.5. Mu.M, 25. Mu.M, 50. Mu.M, and 100. Mu.M of 1-isopropylamino-3- (4-bromo-1-naphthoxy) -2-propanol were treated with MG63, 143B, ACHN, MKN, A375, SK28, SW480, and HT29 cells for 24 hours and 48 hours, respectively.
3) Half-maximal inhibitory concentrations (IC 50) of 1-isopropylamino-3- (4-bromo-1-naphthoxy) -2-propanol and propranolol on different tumor cells
As can be seen from fig. 27, the 1-isopropylamino-3- (4-bromo-1-naphthoxy) -2-propanol (pro+br in fig. 27) provided by the present application has a lower IC50 value (half inhibition concentration) when acting on different tumor cells, relative to propranolol (Pro in fig. 27).
Finally, it should be noted that: the above experimental examples are only for illustrating the technical scheme of the present application, but not for limiting the same; although the present application has been described in detail with reference to the foregoing experimental examples, it will be understood by those skilled in the art that: the technical scheme recorded in each experimental example can be modified or part or all of the technical characteristics can be replaced equivalently; these modifications or substitutions do not depart from the essence of the corresponding technical solutions from the scope of the technical solutions of each experimental example of the present application.

Claims (2)

1. Use of a compound in preparing a medicament for inhibiting tumor cells, wherein the compound is 1-isopropylamino-3- (4-chloro-1-naphthoxy) -2-propanol, and the tumor cells comprise at least one of lung cancer cells, osteosarcoma cells and gastric cancer cells.
2. Use of a compound in the preparation of a medicament for inhibiting tumor cells, wherein the compound is 1-isopropylamino-3- (4-bromo-1-naphthoxy) -2-propanol, and the tumor cells comprise at least one of osteosarcoma cells, gastric cancer cells and melanoma cells.
CN202111427418.7A 2021-11-29 2021-11-29 Compound, pharmaceutical composition containing compound and application of compound Active CN113943227B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN202111427418.7A CN113943227B (en) 2021-11-29 2021-11-29 Compound, pharmaceutical composition containing compound and application of compound

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN202111427418.7A CN113943227B (en) 2021-11-29 2021-11-29 Compound, pharmaceutical composition containing compound and application of compound

Publications (2)

Publication Number Publication Date
CN113943227A CN113943227A (en) 2022-01-18
CN113943227B true CN113943227B (en) 2023-11-07

Family

ID=79338815

Family Applications (1)

Application Number Title Priority Date Filing Date
CN202111427418.7A Active CN113943227B (en) 2021-11-29 2021-11-29 Compound, pharmaceutical composition containing compound and application of compound

Country Status (1)

Country Link
CN (1) CN113943227B (en)

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU2005201855A1 (en) * 2004-09-21 2006-04-06 Marshall Edwards, Inc. Chroman derived compounds and formulations thereof for use in therapy
WO2006083924A1 (en) * 2005-02-02 2006-08-10 Vitae Pharmaceuticals, Inc. 1-acylamino-2-hydroxy-3-amino-w-arylalkanes as renin inhibitors
CN105503863A (en) * 2015-12-11 2016-04-20 南京华威医药科技开发有限公司 Novel anti-tumor compound
CN108586273A (en) * 2018-03-07 2018-09-28 江南大学 A kind of preparation method of Propranolol Hydrochloride
CN109970857A (en) * 2017-12-27 2019-07-05 信达生物制药(苏州)有限公司 Anti- PD-L1 antibody and application thereof
CN112573978A (en) * 2019-09-30 2021-03-30 北京大学 High-efficiency halogenation synthesis method of aryl halide

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2484678B1 (en) * 2009-09-28 2015-01-21 Qilu Pharmaceutical Co., Ltd 4-(substituted anilino)quinazoline derivatives as tyrosine kinase inhibitors

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU2005201855A1 (en) * 2004-09-21 2006-04-06 Marshall Edwards, Inc. Chroman derived compounds and formulations thereof for use in therapy
WO2006083924A1 (en) * 2005-02-02 2006-08-10 Vitae Pharmaceuticals, Inc. 1-acylamino-2-hydroxy-3-amino-w-arylalkanes as renin inhibitors
CN105503863A (en) * 2015-12-11 2016-04-20 南京华威医药科技开发有限公司 Novel anti-tumor compound
CN109970857A (en) * 2017-12-27 2019-07-05 信达生物制药(苏州)有限公司 Anti- PD-L1 antibody and application thereof
CN108586273A (en) * 2018-03-07 2018-09-28 江南大学 A kind of preparation method of Propranolol Hydrochloride
CN112573978A (en) * 2019-09-30 2021-03-30 北京大学 High-efficiency halogenation synthesis method of aryl halide

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
J m s P. Bloxsidge et al..TRITIUM NUCLEAR MAGETIC RESONANCE SPECTROSCOPY. PART 13 [ref.(1)] TRITIUM LABELLED NEUROCHEMICALS.《Journal of Labelled Compounds and Radiopharmaceuticals》.1981,第1141-1165页. *
Joseph Ciccolini et al..Drug repositioning: Propanolol potentiates the anticancer efficacy of chemotherapeutic agents through modulation of angiogenesis.《Cancer Res》.2011,第2555页. *
Song Song et al..DMSO-catalysed late-stage chlorination of (hetero)arenes.《Nature Catalys》.2020,第3卷第107-115页. *
芳氨基代-α-呋喃葡萄糖衍生物的合成及抗肿瘤活性;孙宝丽;张娅玲;王丽丽;张喜全;顾红梅;李宝林;;应用化学(第09期);987-993 *

Also Published As

Publication number Publication date
CN113943227A (en) 2022-01-18

Similar Documents

Publication Publication Date Title
KR100668400B1 (en) Tetrahydropyridoethers
US4511582A (en) Phenanthrene derivatives
BR112021006710A2 (en) compounds analogous to iludin, uses thereof and methods for synthesizing them
WO2015096640A1 (en) Thiazolyl-containing rapamycin derivative and application thereof
CN110467633B (en) Main group metal complex and preparation method and application thereof
KR20170090535A (en) Method of preparing (+)-1,4-dihydro-7-[(3s,4s)-3-methoxy-4-(methylamino)-1-pyrrolidinyl]-4-oxo-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylic acid
CN112174940A (en) 3- (6, 7-bis (2-methoxyethoxy) -quinazoline-4-amido) phenyl-1H-triazole derivative
CN113943227B (en) Compound, pharmaceutical composition containing compound and application of compound
US20090325996A1 (en) Camptothecin derivatives and their use
CN110563679B (en) Sesquiterpene lactone compound, preparation method thereof and application of sesquiterpene lactone compound in preparation of medicine for preventing and treating nasopharyngeal carcinoma
CN111196922B (en) Application of pH-sensitive beta-carboline derivative fluorescent probe in tumor fluorescence imaging
CN114478561B (en) Epalrestat lycorine conjugate and preparation method and application thereof
EP0618901A1 (en) Highly water soluble bis-naphthalimides useful as anticancer agents.
CN115433207A (en) Macrocyclic heterocyclic compound as EGFR inhibitor and application thereof
CN111499608B (en) Benzo [ c ] benzopyrone derivatives and application thereof
CN115667275A (en) Boron-containing compounds and their use
US7326403B2 (en) Radioactive iodine-labeled compound
CN114573459B (en) Beta-elemene diamido substituted derivative and preparation method and application thereof
RU2608308C2 (en) Diazonium amide analogues
CN115536699B (en) Novel EGFR-TKIs, preparation method, pharmaceutical composition and application thereof
CN111285900B (en) Coupling molecule DCZ0847 compound based on pterostilbene and apocynin, preparation method and application thereof
JP2781073B2 (en) Novel quinoline derivative and anticancer drug effect enhancer containing the same as active ingredient
KR101667480B1 (en) A pyrazoline-1-carbothioamide naphthochalcone derivative and use of the same for anticancer treatment
CN114456184A (en) 3-aryl isoquinoline derivative and preparation and application thereof
CN117247319A (en) 5, 6-dihydroxynaphthoate compound and preparation method and application thereof

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
GR01 Patent grant
GR01 Patent grant